Therapeutic agents

ABSTRACT

Compounds of formula I ##STR1## in which R 1  is C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, cycloalkylalkyl or optionally substituted phenyl; R 2  is H or C 1-3  alkyl; R 3  and/or R 4  are H, formyl, C 1-3  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, C 3-7  cycloalkyl or R 3  and R 4  together with the nitrogen atom form a heterocyclic ring system; R 5  and/or R 6  are H, halo, CF 3 , C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylthio or R 5  and R 6  together with the carbon atoms to which they are attached form a second benzene ring show therapeutic acitivity in the treatment of depression. Pharmaceutical compositions and processes for preparing compounds of formula I are disclosed.

This is a continuation of application Ser. No. 365,285, filed Apr. 5,1982, now U.S. Pat. No. 4,522,828.

This invention relates to compounds having useful therapeutic activityas antidepressants, to pharmaceutical compositions containing suchcompounds and to processes for the preparation of such compounds.

The present invention provides compounds of formula I ##STR2## in whichR₁ is a straight or branched chain alkyl group containing 1 to 6 carbonatoms, a cycloalkyl group containing 3 to 7 carbon atoms, acycloalkylalkyl group in which the cycloalkyl group contains 3 to 6carbon atoms and the alkyl group contains 1 to 3 carbon atoms, analkenyl group or an alkynyl group containing 2 to 6 carbon atoms or agroup of formula II ##STR3## in which R₉ and R₁₀, which may be the sameor different, are H, halo or an alkoxy group containing 1 to 3 carbonatoms;

in which R₂ is H or an alkyl group containing 1 to 3 carbon atoms;

in which R₃ and R₄, which may be the same or different, are H, astraight or branched chain alkyl group containing 1 to 4 carbon atoms,an alkenyl group having 3 to 6 carbon atoms, an alkynyl group having 3to 6 carbon atoms, a cycloalkyl group in which the ring contains 3 to 7carbon atoms, a group of formula R₁₁ CO where R₁₁ is H or R₃ and R₄together with the nitrogen atom to which they are attached form anoptionally substituted heterocyclic ring having 5 or 6 atoms in the ringwhich may contain further hetero atoms in addition to the nitrogen atom:in which R₅ and R₆, which may be the same or different, are H, halo,trifluoromethyl, an alkyl group containing 1 to 3 carbon atoms, analkoxy or alkylthio group containing 1 to 3 carbon atoms, phenyl, or R₅and R₆, together with the carbon atoms to which they are attached, forma second benzene ring which may be substituted by one or more halogroups, an alkyl or alkoxy group containing 1 to 4 carbon atoms or thesubstituents of the second benzene ring together with the two carbonatoms to which they are attached may form a further benzene ring;

and their pharmaceutically acceptable salts.

In the formulae included in this specification the symbol ##STR4##represents a 1,1-disubstituted cyclobutane group of formula ##STR5## and--CR₁ R₂.NR₃ R₄ represents a group of formula ##STR6##

In the preferred compounds of formula I R₁ is a straight or branchedchain alkyl group containing 1 to 4 carbon atoms, a cycloalkyl groupcontaining 3 to 7 carbon atoms, a cycloalkylmethyl group in which thecycloalkyl ring contains 3 to 6 carbon atoms or a group of formula II inwhich R₉ and/or R₁₀ are H, fluoro or methoxy and in which R₂ is H ormethyl. Examples of particularly preferred compounds of formula I arethose in which R₂ is H and R₁ is methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, isobutyl cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl or phenyl.

In preferred compounds of formula I, R₃ and/or R₄ are hydrogen, methyl,ethyl or formyl or R₃ and R₄ together with the nitrogen atom to whichthey are attached form a heterocyclic ring containing one nitrogen atomand 4 or 5 carbon atoms which is optionally substituted by one or morealkyl groups or R₃ and R₄ together with the nitrogen atom to which theyare attached form a heterocyclic ring containing a second nitrogen atomwhich is optionally alkylated or a heterocyclic ring including one ormore double bonds.

In preferred compounds of formula I R₅ and/or R₆ are H, fluoro, chloro,bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or R₅ and R₆together with the carbon atoms to which they are attached form a secondbenzene ring which may optionally be substituted by halo.

A first group of preferred compounds of formula I is represented byformula III ##STR7## in which R₅ and R₆ are as defined above. Inpreferred compounds of formula III R₅ and R₆, which may be the same ordifferent, are H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl,methoxy, phenyl or in which R₅ and R₆ together with the carbon atoms towhich they are attached form a second benzene ring which may optionallybe substituted by a chloro group. In particularly preferred compounds offormula III R₅ and/or R₆ are H, fluoro, chloro, iodo, trifluoromethyl,methyl, phenyl or R₅ and R₆ together with the carbon atoms to which theyare attached form a second benzene ring which may optionally besubstituted by a chloro group.

A second group of preferred compounds of formula I is represented byformula IV ##STR8## in which R₅ may be H, fluoro, chloro, bromo, iodo,trifluoromethyl, methyl, methoxy or phenyl and in which R₆ is fluoro ormethyl. In particular preferred compounds of formula IV R₅ is H orchloro.

Compounds of formula I may exist as salts with pharmaceuticallyacceptable acids. Examples of such salts include hydrochlorides,maleates, acetates, citrates, fumarates, tartrates, succinates and saltswith acidic amino acids such as aspartic and glutamic acids.

Compounds of formula I which contain one or more asymmetric carbon atomscan exist in different optically active forms. When R₁ and R₂ aredifferent or R₇ and R₈ are different, the compounds of formula I containa chiral centre. Such compounds exist in two enantiomeric forms and thepresent invention includes both enantiomeric forms and mixtures thereof.When R₁ and R₂ are different and R₁ contains a chiral centre thecompounds of formula I contain two chiral centres and the compoundsexist in four diastereoisomeric forms. The present invention includeseach of these diastereoisomeric forms and mixtures thereof.

The present invention also includes pharmaceutical compositionscontaining a therapeutically effective amount of a compound of formula Itogether with a pharmaceutically acceptable diluent or carrier.

In therapeutic use, the active compound may be administered orally,rectally, parenterally or topically, preferably orally. Thus thetherapeutic compositions of the present invention may take the form ofany of the known pharmaceutical compositions for oral, rectal,parenteral or topical administration. Pharmaceutically acceptablecarriers suitable for use in such compositions are well known in the artof pharmacy. The compositions of the invention may contain 0.1-90% byweight of active compound. The compositions of the invention aregenerally prepared in unit dosage form.

Compositions for oral administration are the preferred compositions ofthe invention and these are the known pharmaceutical forms for suchadministration, for example tablets, capsules, syrups and aqueous oroily suspensions. The excipients used in the preparation of thesecompounds are the excipients known in the pharmacists' art. Tablets maybe prepared by mixing the active compound with an inert diluent such ascalcium phosphate in the presence of disintegrating agents, for examplemaize starch, and lubricating agents, for example magnesium stearate,and tableting the mixture by known methods. The tablets may beformulated in a manner known to those skilled in the art so as to give asustained release of the compounds of the present invention. Suchtablets may, if desired, be provided with enteric coatings by knownmethods, for example by the use of cellulose acetate phthalate.Similarly, capsules, for example hard or soft gelatin capsules,containing the active compound with or without added excipients, may beprepared by conventional means and, if desired, provided with entericcoatings in a known manner. The tablets and capsules may convenientlyeach contain 1 to 500 mg of the active compound. Other compositions fororal administration include, for example, aqueous suspensions containingthe active compound in an aqueous medium in the presence of a non-toxicsuspending agent such as sodium carboxymethylcellulose, and oilysuspensions containing a compound of the present invention in a suitablevegetable oil, for example arachis oil.

Compositions of the invention suitable for rectal administration are theknown pharmaceutical forms for such administration, for examplesuppositories with cocoa butter or polyethylene glycol bases.

Compositions of the invention suitable for parenteral administration arethe known pharmaceutical forms for such administration, for examplesterile suspensions in aqueous and oily media or sterile solutions in asuitable solvent.

Compositions for topical administration may comprise a matrix in whichthe pharmacologically active compounds of the present invention aredispersed so that the compounds are held in contact with the skin inorder to administer the compounds transdermally. Alternatively theactive compounds may be dispersed in a pharmaceutically acceptable creamor ointment base.

In some formulations it may be beneficial to use the compounds of thepresent invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

In the compositions of the present invention the active compound may, ifdesired, be associated with other compatible pharmacologically activeingredients.

The pharmaceutical compositions containing a therapeutically effectiveamount of a compound of formula I may be used to treat depression inmammals including human beings. In such treatment the amount of thecompound of formula I administered per day is in the range 1 to 1000 mgpreferably 5 to 500 mg.

Compounds of formula I in which R₄ is CHO may be prepared by thereductive amidation of ketones of formula V ##STR9## for example withformamide and formic acid or ammonium formate and formic acid to givecompounds of formula I in which R₄ is CHO and R₃ is H or with formamidesof formula HCONHR₃ in which R₃ is an alkyl or cycloalkyl group andformic acid or amines of formula R₃ NH₂ in which R₃ is an alkyl orcycloalkyl group and formic acid.

Compounds of formula I in which R₄ is CHO may be prepared by theformylation of compounds of Formula I in which R₄ is H for example byreaction with methyl formate.

Compounds of formula I in which R₃ is other than H and R₄ is CHO may beprepared by reacting compounds of formula I in which R₃ is H and R₄ isCHO with a compound of formula R₃ X where X is a leaving group such as ahalo group in the presence of a base.

Compounds of formula I may be prepared by the reductive amination ofketones of formula V.

Examples of suitable reductive amination processes are given below:

(a) for compounds of formula I in which R₃ and R₄ are H, by reaction ofthe ketone with an ammonium salt for example ammonium acetate and areducing agent such as sodium cyanoborohydride,

(b) for compounds of formula I in which R₃ is alkyl or cycloalkyl and R₄is H by reaction of the ketone with an amine of formula R₃ NH₂ and areducing agent such as sodium cyanoborohydride or sodium borohydride,

(c) for compounds of formula I in which neither R₃ nor R₄ is hydrogen orin which R₃ and R₄ together with the nitrogen atom form a heterocyclicring, by reaction of the ketone with an amine of formula HNR₃ R₄ andeither formic acid or a reducing agent such as sodium cyanoborohydride,

(d) for compounds of formula I in which one or both of R₃ and R₄ are Hor an alkyl or a cycloalkyl group or in which R₃ and R₄ together withthe nitrogen atom form a heterocyclic ring, by catalytic hydrogenationat elevated temperature and pressure of a mixture of the ketone and anamine of formula HNR₃ R₄.

Compounds of formula I in which R₃ and R₄ are both alkyl groups may beprepared by reacting a ketone of formula V with a dialkyl formamide offormula HCONR₃ R₄ for example in the presence of formic acid.

Compounds of formula I may be prepared by the reduction of compounds offormula VI ##STR10## in which (a) Z is a group of formula --CR₁ ═NOH oran ester or ether thereof to give compounds of formula I in which R₂, R₃and R₄ are H;

(b) Z is a group of formula --CR₁ ═NR₃ (where R₃ is other than H or CHO)to give compounds of formula I in which R₂ and R₄ are H;

(c) Z is a group of formula --CR₁ ═NY in which Y represents ametal-containing moiety derived from an organometallic reagent to givecompounds of formula I in which R₂, R₃ and R₄ are H;

Suitable reducing agents for the above reactions include sodiumborohydride, sodium cyanoborohydride, or lithium aluminium hydride.

In (c) above Y is preferably MgBr derived from a Grignard reagent or Liderived from an organolithium compound.

Compounds of formula I may be prepared by the reaction of anorganometallic reagent for example a Grignard reagent of formula R₁ MgXwhere X is Cl, Br or I or an organolithium compound of formula R₁ Liwith an imine of formula VII ##STR11## followed by hydrolysis to give asecondary amine of formula I.

Compounds of formula I in which R₃ and R₄ are H may be prepared by thedecarboxylative rearrangement, for example usingiodosobenzene-bistrifluoroacetate or by a Hofmann reaction using brominein alkaline solution, of amides of formula VIII ##STR12##

Compounds of formula I in which R₃ and R₄ are H may be prepared by thedecarboxylative rearrangement of acyl azides in the Curtius reaction.The acyl azides may be formed for example by reaction of acid chloridesof formula IX with sodium azide. ##STR13##

Compounds of formula I in which R₃ and R₄ are H may be prepared by aSchmidt reaction in which carboxylic acids of formula X react withhydrazoic acid ##STR14##

Compounds of formula I in which R₄ is H may be prepared by hydrolysis ofcompounds of formula I in which R₄ is CHO, for example by acidhydrolysis.

Compounds of formula I in which R₄ is methyl may be prepared byreduction of compounds of formula I in which R₄ is CHO, for example bylithium aluminium hydride or by sodium bis(2-methoxyethoxy)aluminiumhydride.

Compounds of formula I in which one or both of R₃ and R₄ is other than Hmay be prepared from compounds of formula I in which one or both of R₃and R₄ are hydrogen by methods which are well known in the art for theconversion of primary to secondary or tertiary amines or for theconversion of secondary to tertiary amines. The following are given asexamples of suitable processes:

(a) by alkylating primary amines of formula I to give secondary aminesof formula I for example by a process which includes the steps ofprotecting the primary amine with a protecting group such astrifluoroacetyl, alkylating with an alkyl halide and removing theprotecting group for example by hydrolysis;

(b) by alkylating primary amines of formula I, for example, with analkyl halide to give tertiary amines of formula I in which R₃ and R₄ arethe same;

(c) by alkylating secondary amines of formula I, for example, with analkyl halide to give tertiary amines of formula I in which R₃ and R₄ maybe different;

(d) by reacting primary amines of formula I with sodium borohydride andacetic acid to give secondary amines of formula I in which R₃ is ethyland R₄ is H;

(e) by reacting primary amines of formula I with formaldehyde and formicacid to give tertiary amines of formula I in which both R₃ and R₄ aremethyl

(f) by reacting secondary amines of formula I in which R₄ is H withformaldehyde and formic acid to give tertiary amines of formula I inwhich R₄ is methyl

(g) by formylating primary amines of formula I, for example by reactionwith methyl formate, and reducing the resulting formamides, for examplewith lithium aluminium hydride to give secondary amines of formula I inwhich R₃ is methyl and R₄ is H;

(h) by formylating secondary amines of formula I, for example byreaction with methyl formate, and reducing the resulting formamides, forexample with lithium aluminium hydride to give tertiary amines offormula I in which R₄ is methyl.

(i) by acylating primary amines of formula I, for example by reactionwith an acyl chloride of formula R₁₂ COCl or an anhydride of formula(R₁₂ CO)₂ O in which R₁₂ is an alkyl, alkenyl or alkynyl group andreducing the resulting amides for example with lithium aluminium hydrideto give secondary amines of formula I in which R₃ is --CH₂ R₁₂ and R₄ isH.

(j) by acylating secondary amines of formula I in which R₄ is H forexample by reaction with an acyl chloride of formula R₁₂ COCl or ananhydride of formula (R₁₂ CO)₂ O in which R₁₂ is an alkyl, alkenyl oralkynyl group and reducing the resulting amides for example with lithiumaluminium hydride to give tertiary amines in which R₄ is CH₂ R₁₂ ;

(k) by reacting primary amines of formula I with an aldehyde of formulaR₁₃ CHO in which R₁₃ may be an alkyl group, an alkenyl or alkynyl groupor with a ketone of formula R₁₄ COR₁₅ in which R₁₄ and R₁₅ which may bethe same or different are an alkyl group, alkenyl group, alkynyl groupor R₁₄ and R₁₅ together with carbon atom to which they are attached forman alicyclic ring and reducing the resulting imines or enamines forexample with sodium cyanoborohydride or, when R₁₃, R₁₄ or R₁₅ are notalkenyl or alkynyl, by catalytic hydrogenation to give secondary aminesof formula I in which R₃ is R₁₃ CH₂ -- and ##STR15## respectively; (l)by reacting primary amines of formula I with a nongeminallydisubstituted alkane containing 2 or 3 carbon atoms between the carbonatoms carrying the substituents which may be for example halo preferablybromo, or p-toluenesulphonyloxy to give compounds of formula I in whichR₃ and R₄ together with the nitrogen to which they are attached fo aheterocyclic ring containing no heteroatoms other than the nitrogenatom.

The ketones of formula V may be prepared by the hydrolysis of imines offormula XI ##STR16## in which Y represents a metal-containing moietyderived from an organometallic reagent. The imines of formula XI may beprepared by the reaction of said organometallic reagent with a cyanocompounds of formula XII ##STR17## Suitable organometallic reagentsinclude Grignard reagents of formula R₁ MgX where X is Cl, Br or I(Y=MgX) and organolithium compounds of formula R₁ Li (Y=Li).

Ketones of formula V may be prepared by the reaction of carboxylic acidderivatives such as amides or acid halides with an organometallicreagent for example by the reaction of an acid chlorides of formula XIII##STR18## with a Grignard reagent of formula R₁ MgX where X is Cl, Br orI at low temperatures or by the reaction of carboxylic acids of formulaXIV ##STR19## with an organometallic reagent, for example anorganolithium compound of formula R₁ Li.

Ketones of formula V in which R₁ is alkyl (e.g. methyl may be preparedby the reaction of a diazoalkane (e.g. diazomethane) with aldehydes offormula XV ##STR20##

Compounds of formula VI in which Z is a group of formula --CR₁ ═NOH orethers or esters thereof may be prepared by the reaction ofhydroxylamine or an ether or ester thereof with ketones of formula V.

Compounds of formula VI in which Z is a group of formula --CR₁ ═NR₃ maybe prepared by the reaction of amines of formula R₃ NH₂ with ketones offormula V.

The preparation of compounds of formula VI in which Z is a group offormula --CR₁ ═NY has been described above in respect of compounds offormula XI.

Imines of formula VII may be prepared by reaction of amines of formulaR₃ NH₂ with aldehydes of formula XV.

Amides of formula VIII may be prepared by the reaction of ammonia withcarboxylic acid derivatives for example acid chlorides of formula IX orthey may be prepared from cyano compounds of formula XVI for example byhydration with aqueous acids or by reaction with hydrogen peroxide inthe presence of a base. ##STR21##

Carboxylic acids of formula X and XIV may be prepared by the hydrolysis,for example basic hydrolysis, of cyano compounds of formula XVI and XIIrespectively. Carboxylic acids of formula X may be prepared by thereaction of amides of formula VIII with nitrous acid. Carboxylic acidsof formula XIV may be prepared by the reaction of nitrous acid with theamides formed by (a) the reaction of ammonia with carboxylic acidderivatives for example acid chlorides of formula XIII or (b) by thereaction of cyano compounds of formula XII with hydrogen peroxide in thepresence of a base.

Cyano compounds of formula XII may be prepared by the reaction of cyanocompounds of formula XVII ##STR22## with a 1,3-disubstituted propane forexample 1,3-dibromopropane and a base such as sodium hydride.

Cyano compounds of formula XVIII ##STR23## may be prepared from cyanocompounds of formula XII by for example the following series ofreactions

(a) hydrolysis of the cyano group to form a carboxylic acid of formulaXIV;

(b) reduction of the carboxylic acid for example with lithium aluminiumhydride or borane-dimethylsulphide complex to form the correspondingalcohol;

(c) replacement of the hydroxy group of the alcohol by a leaving groupfor example a p-toluene sulphonyloxy group and

(d) replacement of the leaving group with a cyano group. Cyano compoundsof formula XVI in which one or both of R₁ and R₂ are other than H may beprepared from the corresponding cyano compounds of formula XVI in whichR₁ and/or R₂ are H, for example by alkylation with an alkyl halide inthe presence of a base such as lithium diisopropylamide.

Cyano compounds of formula XVI in which R₂ =H may also be prepared byreacting ketones of formula V with a reagent for introducing a cyanogroup such as p-toluenesulphonylmethyl isocyanide.

Acid chlorides of formula XIII and IX may be prepared by the reaction ofcarboxylic acids of formula XIV and X respectively with for examplethionyl chloride.

Aldehydes of formula XV may be prepared by methods well known to thoseskilled in the art. The following are given as examples of suitablemethods:

(a) by the reduction of cyano compounds of formula XII with for exampledi-tert-butylaluminium hydride or diisobutylaluminium hydride.

(b) by the reduction of carboxylic acid derivatives, for example

(i) by the reduction of tertiary amides formed by the reaction ofsecondary amines with acid chlorides of formula XIII for example whenthe secondary amine is a dialkylamine using lithiumdiethoxyaluminohydride as reducing agent or when the secondary amine isethyleneimine using lithium aluminium hydride as the reducing agent,

(ii) by the reaction of acid chlorides of formula XIII for example withlithium tri-tert butoxyaluminohydride.

(c) by the oxidation of alcohols (prepared by the reduction ofcarboxylic acids of formula XIV) with, for example, chromiumtrioxide-pyridine complex in dichloromethane under anhydrous conditions.

Ketones of formula V (except those in which R₅ and R₆ are H and R₁ ismethyl or ethyl), the compounds of formula VI (except those in which Zis CR₁ =NY and R₅ and R₆ are H and R₁ is methyl and ethyl), the iminesof formula VII (except those in which R₅ and R₆ are H), and XI (exceptthose in which R₅ and R₆ are H and R₁ is methyl or ethyl), the amides offormula VIII, the carboxylic acids of formula X (except those in whichR₁, R₂, R₅ and R₆ are H), the cyano compounds of formula XVI and theacid chlorides of formula IX (except those in which R₁, R₂, R₅ and R₆are H) which are described herein as intermediates are novel compounds.Some of the cyano compounds of formula XII and XVII are novel compounds.Such novel compounds form a further aspect of the present invention.

Novel formamides of formula XIX ##STR24## are described herein asintermediates, in the preparation of compounds of formula I and suchnovel formamides form a further aspect of the present invention.

The therapeutic activity of the compounds of formula I has beenindicated by assessing the ability of the compounds to reverse thehypothermic effects of reserpine in the following manner. Male mice ofthe Charles River CDl strain weighing between 18 and 30 grammes wereseparated into groups of five and were supplied with food and water adlibitum. After five hours the body temperature of each mouse was takenorally and the mice were injected intraperitoneally with reserpine (5mg/kg) in solution in deionised water containing ascorbic acid (50mg/ml). The amount of liquid injected was 10 ml/kg of body weight. Ninehours after the start of the test food was withdrawn but water was stillavailable ad libitum. Twenty-four hours after the start of the test thetemperatures of the mice were taken and the mice were given the testcompound suspended in a 0.25% solution of hydroxy ethyl cellulose (soldunder the trade name Cellosize QP 15000 by Union Carbide) in deionisedwater at a dose volume of 10 ml/kg of body weight. Three hours later thetemperatures of all the mice were again taken. The percentage reversalof the reserpine-induced loss of body temperature is then calculated bythe formula: ##EQU1## The mean value for each group of five mice wastaken at several dose rates to enable a value of the mean dose whichcauses a 50% reversal (ED50) to be obtained. All the compounds which arethe final products of the Examples hereinafter gave values of ED50 of 30mg/kg or less. It is widely understood by those skilled in the art thatthis test is indicative of compounds having antidepressant activity inhumans.

Table I lists compounds of formula I which gave a value of ED50 in theabove test of 10 mg/kg or less.

Table I

1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride

N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride

N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylaminehydrochloride

1-[1-(4-iodophenyl)cyclobutyl]ethylamine hydrochloride

N-methyl-1-[1-(4-iodophenyl)cyclobutyl]ethylamine hydrochloride

N,N-dimethyl-1-[1-(4-iodophenyl)cyclobutyl]ethylamine hydrochloride

N-methyl-1-[1-(2-naphthyl)cyclobutyl]ethylamine hydrochloride

N,N-dimethyl-1-[1-(4-chloro-3-trifluoromethylphenyl)cyclobutyl]ethylaminehydrochloride

1-[1-(4-chlorophenyl)cyclobutyl]butylamine hydrochloride

N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine hydrochloride

N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine hydrochloride

1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine hydrochloride

N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine hydrochloride

N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylaminehydrochloride

1-[1-(4-biphenylyl)cyclobutyl]butylamine hydrochloride

N,N-dimethyl-1-[1-(4-biphenylyl)cyclobutyl]butylamine hydrochloride

1-[1-(4-chloro-3-fluorophenyl)cyclobutyl]butylamine hydrochloride

N-formyl-1-[1-(4-chloro-3-fluorophenyl)cyclobutyl]butylamine

1-[1-(3-chloro-4-methylphenyl)cyclobutyl]butylamine hydrochloride

N-formyl-1-[1-phenylcyclobutyl]butylamine

1-[1-(3-trifluoromethylphenyl)cyclobutyl]butylamine hydrochloride

1-[1-(naphth-2-yl)cyclobutyl]butylamine hydrochloride

1-[1-(6-chloronaphth-2-yl)cyclobutyl]butylamine

N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-2-methylpropylaminehydrochloride

1-[1-(4-chlorophenyl)cyclobutyl]pentylamine hydrochloride

N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]pentylamine hydrochloride

N,N-dimethyl-1-[1-phenylcyclobutyl]-3-methylbutylamine hydrochloride

1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride

N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride

N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride

N-formyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine

N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride

N-methyl-1-[1-(naphth-2-yl)cyclobutyl]-3-methylbutylamine hydrochloride

N-methyl-1-[1-(3,4-dimethylphenyl)cyclobutyl]-3-methylbutylaminehydrochloride

[1-(4-chlorophenyl)cyclobutyl](cyclopropyl)methylamine hydrochloride

N-methyl-[1-(4-chlorophenyl)cyclobutyl](cyclopentyl)methylaminehydrochloride

[1-(4-chlorophenyl)cyclobutyl](cyclohexyl)methylamine hydrochloride

N-methyl-[1-(4-chlorophenyl)cyclobutyl](cyclohexyl)methylaminehydrochloride

[1-(3,4-dichlorophenyl)cyclobutyl](cyclohexyl)methylamine hydrochloride

N-methyl-[1-(3,4-dichlorophenyl)cyclobutyl](cyclohexyl)methylaminehydrochloride

[1-(4-chlorophenyl)cyclobutyl](cycloheptyl)methylamine hydrochloride

1-[1-(4-chlorophenyl)cyclobutyl]-2-cyclopropylethylamine hydrochloride

N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-2-cylcohexylethylaminehydrochloride

α-[1-(4-chlorophenyl)cyclobutyl]benzylamine hydrochloride

N-methyl-α-[1-(4-chlorophenyl)cyclobutyl]benzylamine hydrochloride

1-[1-(4-chloro-2-fluorophenyl)cyclobutyl]butylamine

N,N-dimethyl-1-[1-(4-chloro-2-fluorophenyl)cyclobutyl]butylaminehydrochloride

N-ethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride

N,N-diethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride

The invention will now be illustrated by the following Examples whichare given by way of example only. All compounds were characterised byconventional analytical techniques and gave satisfactory elementalanalyses. All melting and boiling points are expressed in degreesCelsius.

EXAMPLE 1

A solution of 3,4-dichlorobenzyl cyanide (25 g) and 1,3-dibromopropane(15 ml) in dry dimethyl sulphoxide (150 ml) was added dropwise undernitrogen to a stirred mixture of sodium hydride (7.5 g) dispersed inmineral oil (7.5 g) and dimethylsulphoxide (200 ml) at a temperature inthe range 30° to 35° C. The mixture was stirred at room temperature fortwo hours and propan-2-ol (8 ml) and then water (110 ml) were addeddropwise. The mixture was filtered through a diatomaceous earth soldunder the Registered Trade Mark CELITE and the solid residue washed withether. The ether layer was separated, washed with water, dried andevaporated. 1-(3,4-Dichlorophenyl)-1-cyclobutanecarbonitrile (b.p.108°-120° C. at 0.15 Hg) was isolated by distillation. This method is amodification of that described by Butler and Pollatz (J. Org. Chem.,Vol. 36, No. 9, 1971, p. 1308).

The 1-(3,4-dichlorophenyl)-1-cyclobutanecarbonitrile prepared as above(21.7 g) was dissolved in dry ether (50 ml) and the solution was addedunder nitrogen to the product of the reaction of gaseous methyl bromidewith magnesium turnings (3.9 g) in dry ether (150 ml). The mixture wasstirred at room temperature for two hours and then under reflux for twohours. Crushed ice and then concentrated hydrochloric acid (100 ml) wereadded and the mixture heated under reflux for two hours. The ether layerwas separated, washed with water and aqueous sodium bicarbonate, driedand evaporated. 1-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (b.p.108°-110° at 0.2 mm Hg) was isolated by distillation.

1-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (9.1 g) prepared as above,formamide (6.5 ml) and 98% formic acid (3 ml) were heated at 180° C. forsixteen hours to giveN-formyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine. Concentratedhydrochloric acid (20 ml) was added and the mixture heated under refluxfor three hours. The solution was then cooled, washed with ether andsodium hydroxide solution added. The product was extracted with ether,and the ether extract washed with water, dried and evaporated.1-[1-(3,4-Dichlorophenyl)cyclobutyl]ethylamine (b.p. 112°-118° at 0.2 mmHg) was isolated by distillation. The amine was dissolved in propan-2-oland concentrated hydrochloric acid and the solution evaporated todryness to give 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylaminehydrochloride (m.p. 185°-195° C.). (Formula I R₁ =Me; R₂,R₃ and R₄ =H;R₅ =4--Cl; R₆ =3--Cl).

EXAMPLE 1a

The preparation ofN-formyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine (m.p. 124°-125°C.) (Example 1(a) Formula I R₁ =Me; R₂ =H; R₃ =H; R₄ ═CHO; R₅ =4--Cl andR₆ =3--Cl) described above was repeated and the product isolated bycooling the reaction mixture and collecting the solid produced byfiltration. The formamide was then hydrolysed by concentratedhydrochloric acid in industrial methylated spirit to give thehydrochloride salt of 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine.

In a similar manner to that described above in Example Ia in thefollowing compounds were prepared. The conditions for the hydrolysis ofthe formamides which were isolated by appropriate methods are shown inthe footnotes.

    ______________________________________                                         ##STR25##                                                                                                         m.p. of                                  Example                                                                              R.sub.1 R.sub.5                                                                             R.sub.6                                                                            b.p. (free base)                                                                         HCl salt                                                                             Note                              ______________________________________                                        1(b)   methyl  Cl    H    107°/1.2 mm Hg                                                                           A                                 1(c)   n-butyl Cl    H               138-139°                                                                      B                                 1(d)   methyl  I     H               205-207°                                                                      C                                 1(e)   methyl  Cl    CF.sub.3        216-217°                                                                      D                                 ______________________________________                                         A aqueous HCl/industrial methylated spirit                                    B The 1valeryl-1-(4-chlorophenyl)cyclobutane was prepared in                  tetrahydrofuran. Hydrolysis was performed using concentrated                  HCl/industrial methylated spirit.                                             C concentrated HCl/diethyleneglycoldimethyl ether (in a similar manner to     that described later in Example 12).                                          D concentrated HCl/industrial methylated spirit.                         

EXAMPLE 2

The product of Example 1 (4.04 g), water (0.5 ml) and 98% formic acid(3.6 ml) were mixed with cooling. 37-40% Aqueous formaldehyde (3.8 ml)was added and the solution was heated at 85°-95° C. for five hours. Thesolution was evaporated to dryness and the residue acidified withconcentrated hydrochloric acid and the water removed by repeatedaddition of propan-2-ol followed by evaporation in vacuo. Crystals ofN,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylaminehydrochloride (m.p. 211°-213° C.) (Formula I R₁ =Me; R₂ =H; R₃,R₄ =Me;R₅ =4--Cl; R₆ =3--Cl) were isolated.

In a similar way to that described above the compounds of Example 1(b)and 1(d) were converted into the compounds listed below.

    ______________________________________                                         ##STR26##                                                                           Starting                 m.p. of                                                                              b.p. of free                           Example                                                                              Material R.sub.1 R.sub.5                                                                           R.sub.6                                                                           HCl salt                                                                             base                                   ______________________________________                                        2(a)   1(b)     methyl  Cl  H          98-100°/0.5 mm                  2(b)   1(d)     methyl  I   H   260-261°                               ______________________________________                                    

EXAMPLE 3

In a similar manner to that described above in Examples 1 and 2N,N-dimethyl-1-[1-(4-biphenylyl)cyclobutyl]ethylamine hydrochloride(m.p. 196°-197° C.) was prepared. (Formula I R₁ =Me; R₂ =H; R₃,R₄ =Me;R₅ =4-phenyl and R₆ =H).

EXAMPLE 4

1-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (15 g) prepared as describedin Example 1, N-methylformamide (47.5 ml) 98% formic acid (10.3 ml) anda 25% aqueous solution of methylamine (1.5 ml) were mixed and heatedwith stirring at 170°-180° for eight hours. The mixture was cooled andextracted with ether. The ether extract was washed, dried and evaporatedto yield a light yellow oil which was heated under reflux withconcentrated hydrochloric acid (50 ml) for two hours. Industrialmethylated spirit (IMS) (50 ml) was added and the mixture heated underreflux for sixteen hours. The mixture was then cooled to 0° C. and thewhite precipitate collected by filtration, washed with acetone anddried. The product,N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride,had a melting point of 254° to 256° C. (Formula I R₁ =Me; R₂ =H; R₃ =Me;R₄ =H; R₅ =4--Cl and R₆ =3 --Cl).

In a similar manner to that described above the following compounds offormula I were prepared

    ______________________________________                                         ##STR27##                                                                    Ex-                                                                           am-                                  m.p. of                                  ple  R.sub.1                                                                              R.sub.5  R.sub.6                                                                             b.p. of amine                                                                           HCl salt                                                                             Note                              ______________________________________                                        4(a) Me     Cl       H     98-100°/0.15                                                                     240-241°                                                     mm                                                 4(b) Me     H        Cl              269-272°                          4(c) Me     Br       H     96-98°/0.1 mm                               4(d) Me     H        Br              251-255°                          4(e) Me     CF.sub.3 H               219-221°                          4(f) Me     H        CF.sub.3        225-228°                          4(g) Me     (CHCH).sub.2           254-257°                            4(h) Me     Cl       CF.sub.3        198-200°                          4(i) Et     Cl       H               238-240°                          4(j) Pr     Cl       H               228-229°                                                                      A                                 4(k) Bu     Cl       H               152-153°                                                                      A                                 4(l) Me     I        H               242-243°                          ______________________________________                                         Note A                                                                        The starting ketone was prepared in tetrahydrofuran as reaction solvent i     place of ether.                                                          

EXAMPLE 5

A mixture of 70% aqueous ethylamine (50 ml) and water (100 ml) wasgradually mixed with a mixture of 98% formic acid (50 ml) and water (100ml) to give a neutral solution which was evaporated at 100° C./100 mm Hguntil 180 ml of water had been collected. The residue was heated to 140°C. and 1-acetyl-1-(4-chlorophenyl)cyclobutane (10.4 g) prepared in asimilar manner to that described in Example 1 for1-acetyl-1-(3,4-dichlorophenyl)cyclobutane and 98% formic acid (10 ml)were added. The mixture was heated on an oil bath at a temperature of180°-200° C. for sixteen hours. The mixture was distilled until aninternal temperature of 170° C. was obtained and this temperature wasmaintained for two hours. Any volatile material was removed bydistillation at 160° C./20 mm and the residue heated under reflux withconcentrated hydrochloric acid (15 ml) and industrial methylated spirit(IMS) (15 ml) for three hours. The IMS was evaporated on a rotaryevaporator and the residue washed with ether. The aqueous phase wasbrought to pH 12 with sodium hydroxide and extracted with ether. Theether extract was dried and on evaporation yielded a residue which wastreated with aqueous hydrochloric acid to giveN-ethyl-1-[1-(4-chlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p.203°-205° C.) (Formula I (R₁ =Me; R₂ =H; R₃ =Et; R₄ =H; R₅ =4--Cl; R₆=H).

EXAMPLE 6

1-(4-Chlorophenyl)-1-cyclobutanecarbonitrile (15 g) prepared in asimilar manner to the 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile ofExample 1 in dry ether (50 ml) was added to the product of the reactionbetween magnesium turnings (3.18 g) and propyl bromide (15.99 g) in dryether (50 ml). The ether was replaced by tetrahydrofuran and the mixtureheated with stirring under reflux for eighteen hours. The mixture wascooled and ice and then concentrated hydrochloric acid (52 ml) added.The resulting mixture was stirred under reflux for ten hours andextracted with ether. The ether extract yielded a residue from which1-butyryl-1-(4-chlorophenyl)cyclobutane (b.p. 106°-108°/0.3 mm Hg) wasdistilled.

A mixture of the ketone produced as described above (21 g) and 98%formic acid (6 ml) was added over a period of one and a half hours toformamide (15 ml) at 160° C. After completion of the addition thetemperature was raised to 180° to 185° C. and maintained in this rangefor five hours. The mixture was cooled and extracted with chloroform toyield a thick gum which on heating with petroleum ether (b.p. 60°-80°)gave a colourless solid which was recrystallised from petroleum ether(b.p. 60°-80°) to yieldN-formyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine (m.p. 97.5 to 98.5°C.) (Formula I (R₁ =propyl; R₂ =H; R₃ =H; R₄ =CHO; R₅ =4-Cl; R₆ =H).EXAMPLE 7

A solution of 1-(3,4-dichlorophenyl)-1-cyclobutanecarbonitrile preparedas described in Example 1 (35.2 g) in ether (100 ml) was added to asolution of propyl magnesium bromide prepared by the reaction of propylbromide (32 g) with magnesium turnings (6.36 g) in ether (100 ml). Theether was replaced by dry toluene and the mixture heated under refluxfor one hour. Water (200 ml) and then concentrated hydrochloric acid(120 ml) were added and the mixture heated under reflux for one hour.The reaction mixture was extracted with ether and after washing anddrying the extract yielded a residue from which1-butyryl-1-(3,4-dichlorophenyl)cyclobutane (b.p. 120°-128° C. at 0.25mm) was distilled.

The ketone produced as described above (37.0 g) and 98% formic acid (9ml) were added to formamide (23.5 ml) at 170° C. and the temperaturekept at 175°-180° C. for five hours. A further portion of formic acid(4.5 ml) was added and the mixture was maintained at 175°-180° C. for afurther fifteen hours. The mixture was extracted with ether which onevaporation gave a thick oil which was crystallised from petroleum ether(b.p. 60°-80°) to giveN-formyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine having a meltingpoint of 103°-105° C. (Formula I R₁ =propyl; R₂ =H; R₃ =H; R₄ =CHO; R₅=4--Cl and R₆ =3--Cl).

In a similar manner to that described above the following compounds weremade

    ______________________________________                                         ##STR28##                                                                    Example   R.sub.1  R.sub.5   R.sub.6                                                                           m.p. (°C.)                            ______________________________________                                        7(a)      isobutyl Cl        H   110-112°                              7(b)      propyl   Cl        F   115-116°                              7(c)      phenyl   Cl        H   94-96°                                7(d)      propyl   H         H    98-102°                              ______________________________________                                    

EXAMPLE 8

The product of Example 7 (4.0 g) in dry tetrahydrofuran (25 ml) wasadded rapidly to a stirred mixture of lithium aluminium hydride (1.4 g)in dry tetrahydrofuran (25 ml) under nitrogen. The mixture was heatedunder reflux for five hours and then cooled. Water (15 ml) and then 10%sodium hydroxide solution (3 ml) were added and the mixture filteredthrough diatomaceous earth sold under the Registered Trade Mark CELITE.The product was extracted into ether, back extracted into 5Nhydrochloric acid and the aqueous layer was basified and extracted withether. The ether extract yielded an oil which was dissolved inpropan-2-ol (5 ml) and concentrated hydrochloric acid was added to pH 2.Evaporation of the resulting solution gave a white solid which wascollected, washed with acetone and dried. The product wasN-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine hydrochlorideand had a melting point of 234°-235° C. (Formula I R₁ =propyl; R₂ =H; R₃=H; R₄ =Me; R₅ =4--Cl and R₆ =3--Cl)

In a similar manner to that described above the following compounds wereprepared

    ______________________________________                                         ##STR29##                                                                    Example    R.sub.1 R.sub.5   R.sub.6                                                                           m.p. (°C.)                            ______________________________________                                        8(a)       phenyl  Cl        H   275-278°                              8(b)       propyl  Cl        H   223-228°                              ______________________________________                                    

EXAMPLE 9

The product of Example 7 (10 g) in solution in ether (50 ml) was addedto a 70% toluene solution of sodium bis(2-methoxyethoxy)aluminiumhydride sold under the trade mark Red-al (40 ml) at a temperature in therange 25° to 30° C. The mixture was stirred at this temperature for fourhours. Water (25 ml) was added dropwise with cooling and the mixturefiltered through diatomaceous earth (CELITE). Aqueous NaOH was added andan ether extraction performed. The ether extract was washed with waterand back extracted with 5N hydrochloric acid. A white solid (m.p.232°-235 C.) appeared at the interface which was collected. Base wasadded to the aqueous phase and a further ether extraction performed.Evaporation of the ether extract yielded an oil which was dissolved inpropan-2-ol (5 ml) and concentrated hydrochloric acid added to pH 2.Evaporation to dryness gave a white solid (m.p. 233°-236° C.). The whitesolids were combined and recrystallised from propan-2 -ol to yieldN-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine hydrochloride(m.p. 236°-237° C.) (Formula I R₁ =propyl; R₂ =H; R₃ =H; R₄ =Me; R₅=4--Cl and R₆ =3--Cl).

In a similar manner to that described above the following compounds wereprepared. Where the formyl starting material was insoluble in ether, asolution of the reducing agent was added to a stirred suspension of theformyl compound. As the size of the group R₁ is increased thehydrochloride salts of the desired compounds become less soluble in theaqueous phase and more soluble in the organic phase so that appropriatemodifications in the isolation procedure are required as will beapparent to those skilled in the art.

    ______________________________________                                         ##STR30##                                                                    Example R.sub.1       R.sub.5  R.sub.6                                                                             m.p.                                     ______________________________________                                        9(a)    isopropyl     Cl       H     257-259°                          9(b)    sec-butyl     Cl       H     209-212°                          9(c)    isobutyl      Cl       H     225-233°                          9(d)    cyclopentyl   Cl       H     252-256°                          9(e)    n-hexyl       Cl       H     117-118°                          9(f)    4-methoxyphenyl                                                                             Cl       H     264-266°                          9(g)    3-methoxyphenyl                                                                             Cl       H     254-255°                          9(h)    2-methoxyphenyl                                                                             Cl       H     149-153°                          9(i)    cyclohexyl    Cl       H     170-172°                          9(j)    isobutyl      (CHCH).sub.2 256-259°                            9(k)    cyclohexyl    Cl       Cl    223-224°                          9(l)    isobutyl      Me       Me    (1)                                      9(m)    propyl        OMe      H     173-175°                          9(n)    methyl        phenyl   H     116-118°                          ______________________________________                                         (1) Boiling point of free base >150° at 1.0 mm Hg.                

The product of Example 7 (4 g), diethyleneglycoldimethyl ether (25 ml),water (10 ml) and concentrated hydrochloric acid (10 ml) were mixed andheated under reflux for nine hours. The solution was washed with etherand aqueous NaOH added before an ether extraction was performed. Theether extract was washed with brine and water and yielded an oil onevaporation. The oil (3.19 g) was dissolved in a mixture of propan-2-ol(4 ml) and ether (20 ml) and concentrated hydrochloric acid (1.5 ml)added. The solvent was evaporated in vacuo. Repeated dissolution inindustrial methylated spirit and evaporation in vacuo gave a gum whichsolidified on warming in vacuo. The product was recrystallised frompetroleum ether (b.p. 100°-120° C.) and had a melting point of 201°-203°C. The product was 1-[1-(3,4-dichlorophenyl)cyclobutyl]butylaminehydrochloride (Formula I R₁ =propyl; R₂ =H; R₃, R₄ =H; R₅ =4--Cl and R₆=3--Cl).

In a similar manner to that described above the following compounds wereprepared. As the size of the group R₁ is increased the hydrochloridesalts of the desired compounds become less soluble in the aqueous phaseand more soluble in the organic phase so that appropriate modificationsin the isolation procedure are required as will be apparent to thoseskilled in the art.

    ______________________________________                                         ##STR31##                                                                    Example                                                                              R.sub.1    R.sub.5    R.sub.6  m.p.                                    ______________________________________                                        10(a)  isopropyl  Cl         H        200-202°                         10(b)  sec-butyl  Cl         H        178-179°                         10(c)  isobutyl   Cl         H        163-165°                         10(d)  cyclopentyl                                                                              Cl         H        185-210°                                                               (dec)                                   10(e)  phenyl     Cl         H        271-276°                         10(f)  4-methoxy- Cl         H        214-219°                                phenyl                                                                 10(g)  cyclohexyl Cl         H        206-210°                         10(h)  isobutyl   H          H        210-212°                         10(i)  cyclopropyl                                                                              Cl         H        204-206°                         10(j)  propyl     Ph         H        235-236°                         10(k)  propyl     Me         Cl       214-217°                         10(l)  propyl     (CHCH).sub.2      157-159°                           10(m)  cycloheptyl                                                                              Cl         H        156-162°                         10(n)  cyclohexyl Cl         Cl       215°                             10(p)  methyl     Cl         F        215-217°                         10(q)  propyl     OMe        H        178-179°                         10(r)  propyl     Cl         F        186-188°                         10(s)  propyl     Cl         H        174-175°                         10(t)  cyclohexyl-                                                                              Cl         H        148-150°                                methyl                                                                 10(u)  cyclo-     Cl         H        184-185°                                propylmethyl                                                           10(v)  propyl     CHCHCClCH         (a)                                       10(w)  propyl     H          CF.sub.3 126-128°                         10(x)  4-fluoro-  Cl         H        279°                                    phenyl                                                                 10(y) (b)                                                                            methyl                                                                                    ##STR32##        248-262°                           ______________________________________                                         (a) boiling point of free base 168° C./0.05 mm Hg.                     (b) diethyleneglycoldimethyl ether replaced by ethyleneglycoldimethyl         ether.                                                                   

In a similar manner to that described above,1-[1-(4-chloro-2-fluorophenyl)cyclobutyl]butylamine (b.p. 99° C./0.05mm). (Formula I R₁ =propyl; R₂, R₃ and R₄ =H; R₅ =4--Cl; R₆ =2--F),1-[1-(2-fluorophenyl)cyclobutyl]butylamine hydrochloride (m.p. 175°-177°C.). (Formula I R₁ =propyl; R₂, R₃, R₄, R₅ =H and R₆ =2--F) and1-[1-(4-chloro-2-methyl)cyclobutyl]butylamine hydrochloride (m.p.188°-190° C.) (Formula I R₁ =propyl; R₂, R₃ and R₄ =H; R₅ =4--Cl and R₆=2--Me) were prepared as Examples 10(z), 10(aa) and 10(bb) respectively.

EXAMPLE 11

The product of Example 10(c) (3.3 g) in the form of the free base,formic acid (2.99 g) and water (1 ml) were mixed with cooling. 37-40%Aqueous formaldehyde (3.93 ml) was added and the mixture heated foreighteen hours at a temperature of 85°-95° C. Excess dilute hydrochloricacid was added and the solution evaporated to dryness. The residue wasbasified with 5N sodium hydroxide solution and the product was extractedinto ether. Evaporation of the ether yielded a pale yellow oil which wasdissolved in a mixture of propan-2-ol (4 ml) and ether (20 ml) andconcentrated hydrochloric acid (2 ml) was added dropwise. The solutionwas evaporated and the residue dissolved repeatedly in ethanol andevaporated in vacuo to give a gum which was triturated with petroleumether (b.p. 60°-80°) to yield a yellow solid which was recrystallisedfrom acetone. The product wasN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride (m.p. 195°-197° C.). (Formula I R₁ =isobutyl; R₂ =H; R₃,R₄ =Me; R₅ =4--Cl; R₆ =H).

In a similar manner to that described above the following compounds ofFormula I were prepared

    ______________________________________                                         ##STR33##                                                                    Ex-                                                                           am-  Starting                                                                 ple  Material R.sub.1   R.sub.5  R.sub.6  m.p.                                ______________________________________                                        11(a)                                                                              10(h)    isobutyl  H        H        195-                                                                          198°                         11(b)                                                                              10(j)    propyl    Ph       H        194-                                                                          196°                         11(c)                                                                              10(n)    cyclohexyl                                                                              Cl       Cl       227-                                                                          228°                         11(d)                                                                              10(q)    propyl    OMe      H        187-                                                                          188°                         11(e)                                                                              10(s)    propyl    Cl       H        194-                                                                          196°                         11(f)                                                                              10(t)    cyclohexyl                                                                              Cl       H        194-                                              methyl                      196°                         11(g)                                                                              10(u)    cyclo-    Cl       H        165-                                              propyl-                     167°                                       methyl                                                          11(h)                                                                              10(v)    propyl    CHCHCClCH       (a)                                   11(i)                                                                              --       isobutyl  Cl       Cl       225-                                                                          226°                         11(j)                                                                              10(x)    4-fluoro- Cl       H        234°                                       phenyl                                                          11(k)                                                                              --       propyl    isopropyl                                                                              H        211-                                                                          213°                         ______________________________________                                         (a) boiling point of free base <250° C./0.05 mm Hg.               

EXAMPLE 11(1)

In a similar manner to that described aboveN,N-dimethyl-1-[1-(4-chloro-2-fluorophenyl)cyclobutyl]butylaminehydrochloride (m.p. 183°) was prepared. (Formula I R₁ =propyl; R₂ =H;R₃, R₄ =Me; R₅ =4--Cl; R₆ =2--F)

EXAMPLE 12

The product of Example 7 (8.3 g), diethyleneglycoldimethyl ether (50ml), water (20 ml) and concentrated hydrochloric acid (20 ml) were mixedand heated under reflux for sixteen hours. The mixture was poured intowater, aqueous NaOH was added and the product extracted into ether.Evaporation gave a dark oil. A sample of this oil (7.9 g) water (0.7 ml)and formic acid (6.5 ml) were mixed and formaldehyde (6.5 ml) added. Themixture was heated under reflux for three hours and then concentratedhydrochloric acid (10 ml) and propan-2-ol (10 ml) were added.Evaporation to dryness gaveN,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylaminehydrochloride (m.p. 195°-196°) as a white solid (Formula I R₁ =propyl;R₂ =H; R₃, R₄ =Me; R₅ =4--Cl and R₆ =3--Cl).

EXAMPLE 13

1-(4-Chlorophenyl)-1-cyclobutanecarbonitrile (37.6 g) prepared in asimilar manner to the 1-(3,4-dichlorophenyl)-1-cyclobutanecarbonitriledescribed in Example 1 was added to a solution of potassium hydroxide(32.4 g) in diethyleneglycol (370 ml) and the mixture heated underreflux for three and a half hours. The reaction mixture was poured intoan ice/water mixture and the resulting solution was washed with ether.The aqueous layer was added to a mixture of concentrated hydrochloricacid (100 ml) and ice and the resulting precipitate of1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid (m.p. 86°-88°)collected, washed with water and dried.

A solution of the acid (10.5 g) prepared as above in tetrahydrofuran(150 ml) was added dropwise under nitrogen to a stirred suspension oflithium aluminum hydride (2 g) in tetrahydrofuran (150 ml). The mixturewas stirred under reflux for two hours and water added. The mixture wasfiltered through diatomaceous earth (CELITE--RTM) and the productextracted into ether. After washing with water and drying, the ether wasevaporated to give a residue which was recrystallised from petroleumether (b.p. 60°-80°). The product was1-[1-(4-chlorophenyl)cyclobutyl]methyl alcohol (m.p. 60°-62° C.).

A solution of the alcohol prepared as described above (60 g) in pyridine(52 ml) was added dropwise to a solution of p-toluenesulphonylchloride(60 g) in pyridine (100 ml) cooled in ice. The temperature was allowedto rise to room temperature and remain there for eighteen hours.1-[1-(4-Chlorophenyl)cyclobutyl]methyl p-toluene sulphonate (m.p.99°-100° C.) was precipitated by pouring the reaction mixture into amixture of ice and concentrated hydrochloric acid (200 ml).

A solution of the sulphonate compound (97 g) prepared as described aboveand sodium cyanide (16.6 g) in dimethyl sulphoxide (370 ml) was heatedon a steam bath for eighteen hours. The mixture was poured into waterand extracted with ether. After washing and drying the ether wasevaporated to leave a solid residue of2-[1-(4-chlorophenyl)cyclobutyl]acetonitrile (m.p. 63°-65° C.).

A solution of di-isopropylamine (16.5 g) in dry tetrahydrofuran (50 ml)was stirred under nitrogen at a temperature of 0° C. and a 1.6 Msolution of n-butyllithium in hexane (100 ml) added dropwise. Thereaction mixture was stirred for 30 minutes and then cooled to -78° C. Asolution of 2-[1-(4-chlorophenyl)cyclobutyl]acetonitrile (9.5 g)prepared as described above in dry tetrahydrofuran (25 ml) was addeddropwise. The temperature of the mixture was allowed to rise to 0° C.and the mixture was stirred for ten minutes before a solution of methyliodide (10 ml) in tetrahydrofuran (10 ml) was added. Tetrahydrofuran (75ml) was added to give a homogeneous solution and a further solution ofmethyl iodide (4 ml) in tetrahydrofuran (10 ml) added. The mixture wasstirred at ambient temperature for two hours and then water (50 ml)added. The aqueous phase was washed with ether and the ether combinedwith the organic phase of the reaction mixture. The combined organicphases were washed three times with 5N hydrochloric acid, three timeswith water, dried and evaporated to yield an oil which solidified andwas recrystallised from industrial methylated spirit to give2-[1-(4-chlorophenyl)cyclobutyl]-2-methylpropionitrile (m.p. 73°-75°C.).

The nitrile prepared above (4 g) was heated under reflux with potassiumhydroxide (8 g) in diethyleneglycol (40 ml) for 24 hours. The reactionmixture was cooled, added to water (50 ml) and the aqueous phase washedtwice with ether. The aqueous phase was acidified with 5N hydrochloricacid and extracted with three portions of ether. The combined etherextracts were washed with water, dried and evaporated to give a whitesolid which was recrystallised from petroleum ether (b.p. 60°-80°) togive 2-[1-(4-chlorophenyl)cyclobutyl]-2-methylpropionic acid (m.p.95°-110° C.).

Oxalyl chloride (10 ml) was added to the acid (2 g) prepared as aboveand after the initial effervesence had subsided the mixture was heatedunder reflux for one hour. Excess oxalyl chloride was removed bydistillation and the residual oil added to concentrated aqueous ammonia(75 ml). An oily solid formed which was extracted into ethyl acetate.The extract was washed with water, dried and evaporated to give2-[1-(4-chlorophenyl)cyclobutyl]-2-methyl propionamide.

The amide prepared as above (1.34 g) was dissolved in a mixture ofacetonitrile (8 ml) and water (8 ml) and iodosobenzenebistrifluoroacetate (3.4 g) added and the mixture stirred at ambienttemperature for five and a half hours. Water (75 ml) and concentratedhydrochloric acid (8 ml) were added and the mixture extracted withether. The ether extract was washed with 5N hydrochloric acid and theaqueous phase basified and extracted with further portions of etherwhich were dried and evaporated to give an oil. The oil was dissolved inpetroleum ether (b.p. 80°-100°) and dry hydrogen chloride gas passedthrough the solution.1-[1-(4-Chlorophenyl)cyclobutyl]-1-methylethylamine hydrochloride (m.p.257°-259° C.) was collected by filtration (Formula I R₁, R₂ =Me; R₃, R₄=H; R₅ =4--Cl; R₆ =H).

EXAMPLE 14

The product of Example 4(h) (3.4 g) was mixed with anhydrous sodiumformate (0.72 g), 98% formic acid (10 ml) and 37-40% aqueousformaldehyde solution (5 ml) and the mixture heated at a temperature of85°-95° C. for sixteen hours. The mixture was diluted with water (50 ml)and basified to pH 10 with aqueous sodium hydroxide solution. The basicaqueous solution was extracted with ether, washed with water and driedwith magnesium sulphate. Dry hydrogen chloride gas was bubbled throughthe ether extract to give a white precipitate ofN,N-dimethyl-1-[1-(4-chloro-3-trifluoromethylphenyl)cyclobutyl]ethylaminehydrochloride (m.p. 246°-247° C.) (Formula I R₁ =Me; R₂ =H; R₃, R₄ =Me;R₅ =4--Cl and R₆ =3--CF₃).

EXAMPLE 15

The production of salts of the compounds of the invention is illustratedby the following Examples in which equimolar amounts of the base and theacid were taken up in a solvent. The salt was then obtained from thesolution by conventional techniques.

    ______________________________________                                        Exam-                                                                         ple   Base     Acid       Solvent   m.p. of salt                              ______________________________________                                        15(a) 10(s)    citric     aqueous acetone                                                                         158-160°                           15(b) 10(s)    maleic     ether     155-157°                           15(c) 10(s)    succinic   ether     152-155°                           15(d) 2        L(+)tartaric                                                                             I.M.S.    150-153°                           15(e) Note (a) citric     ether/methanol                                                                          163-164°(dec)                      ______________________________________                                    

(a) The base was 1-[1-(3,4-dimethylphenyl)cyclobutyl]-3-methylbutylamineprepared in a similar manner to that described in Example 10.

EXAMPLE 16

A solution of bromobenzene (15.7 g) in ether (50 ml) was added dropwisewith cooling to magnesium turning (2.4 g) under an atmosphere ofnitrogen. A solution of 1-(4-chlorophenyl)-cyclobutanecarbonitrile (19.1g) prepared in a similar manner to that described in Example 1 for the1-(3,4-dichlorophenyl)cyclobutane carbonitrile in ether (50 ml) wasadded and the ether replaced by dry toluene (130 ml). The reactionmixture was heated on a steam bath for one hour. A sample (20 ml) of theresulting solution was added to a solution of sodium borohydride (1 g)in diethyleneglycoldimethyl ether (60 ml) and the mixture was stirredfor one and a half hours. Water (60 ml) was added slowly and the aqueouslayer extracted with toluene. The toluene extracts were washed withwater, dried and evaporated to give a residue which was dissolved inmethanol (50 ml). 6N Hydrochloric acid (5 ml) was added and thesoltution filtered and evaporated. Trituration with dry acetone gaveα-[1 -(4-chlorophenyl)cyclobutyl]benzylamine hydrochloride (m.p.277°-279° C.) (Formula I R₁ =Ph; R₂ =H; R₃, R₄ =H; R₅ =4--Cl; R₆ =H).

EXAMPLE 17

Methyl formate (62 ml) was added dropwise to isopropylamine (85.5 ml)with stirring at a rate which maintained gentle reflux conditions.Stirring was continued for two hours after the addition. Methanol wasdistilled off at 100° C. and N-isopropylformamide (b.p. 108°-109° C./25mm Hg) obtained by distillation.

1-Acetyl-1-(4-chlorophenyl)cyclobutane (10.4 g) prepared in a similarmanner to that described in Example 1 for1-acetyl-1-(3,4-dichlorophenyl)cyclobutane and 98% formic acid (5 ml)were added to N-isopropylformamide (43.5 g) and the mixture heated at180° C. for four hours. Excess starting material was distilled off underreduced pressure (20 mm Hg) to leave a viscous residue which was heatedunder reflux with concentrated hydrochloric acid (30 ml) for six hours.The reaction mixture was washed with ether until a colourless solutionwas obtained. The aqueous phase was basified, extracted with ether,dried and evaporated to give an oil which was dissolved in 5Nhydrochloric acid. On evaporation a yellow oil was obtained which wastriturated with petroleum ether (b.p. 62°-68° C.) to giveN-isopropyl-1-[1-(4-chlorophenyl)cyclobutyl]ethylamine hydrochloride(m.p. 170°-174° C.) (Formula I R₁ =Me; R₂ =H; R₃ =isopropyl; R₄ =H; R₅=4--Cl; R₆ =H).

EXAMPLE 18

1-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (7.0 g) prepared as describedin Example 1 was slowly added to a mixture of pyrrolidine (25 ml) and98% formic acid (15 ml) heated to 130°-135° C. for five hours. Themixture was stirred and heated at 160°-165° C. for sixteen hours. Aftercooling the mixture was poured into 5N hydrochloric acid (200 ml). Thesolution was washed with ether, basified with aqueous sodium hydroxidesolution and extracted with ether. The ether extract was washed withwater, dried and hydrogen chloride gas was passed into the extract whichwas then evaporated to dryness. The residue was triturated with dryether to give a solid which was recrystallised from propan-2-ol to giveN-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethyl pyrrolidine hydrochloride(m.p. 233°-235° C.) (Formula I R₁ =Me; R₂ =H; R₃ and R₄ together withthe nitrogen to which they are attached form a pyrrolidine ring; R₅ =4--Cl and R₆ =3--Cl).

EXAMPLE 19

1-(4-Chlorophenyl)-1-cyclobutane carboxylic acid (10.5 g) prepared asdescribed in Example 13 was heated under reflux with thionyl chloride(20 ml) for 21/2 hours. Excess thionyl chloride was evaporated off andthe acid chloride of the above acid distilled (b.p. 82°-96°/0.2 mm Hg).

A solution of the acid chloride (23.0 g) in dry tetrahydrofuran (100 ml)was added slowly to the product of the reaction of magnesium turnings(3.0 g) and ethyl bromide (12.0 g) in dry tetrahydrofuran at atemperature of -70 to -60° C. The temperature was kept at -60° C. for anhour and was then allowed to rise to 0° C. Water (50 ml) was addedfollowed by 5N hydrochloric acid (150 ml) with cooling. The reactionmixture was extracted with ether, washed with water, sodium bicarbonatesolution, dried. The solvent was removed by evaporation and1-propionyl-1-(4-chlorophenyl)cyclobutane obtained by distillation (b.p.96°-104° C./0.25 mm)

The ketone produced above was converted toN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutylpropylamine hydrochloride(m.p. 213°-215° C.) in a similar manner to that described in Example 12(Formula I R₁ =Et; R₂ =H; R₃, R₄ =Me; R₅ =4--Cl; R₆ =H).

EXAMPLE 20

1-Acetyl-1-(4-chlorophenyl)cyclobutane (61 g prepared in a similarmanner to that described in Example 1 for1-acetyl-1-(3,4-dichlorophenyl)cyclobutane, platinum oxide (0.75 g), 33%solution of methylamine in ethanol (60 g) and ethanol (30 ml) werecharged into an autoclave. The autoclave was filled with hydrogen andmaintained at about 60° C. and 20 bar pressure for ten hours. Thereaction mixture was filtered through charcoal and the solids washedwith absolute alcohol. The solvents were removed by evaporation and asample of the residue (10 g) was shaken with 2M hydrochloric acid (50ml) and ether (50 ml). The aqueous layer was basified and extracted withether. The ether extract yielded a liquid on evaporation which wasdistilled (109° C./0.3 mm Hg) to giveN-methyl-1-[1-(4-chlorophenyl)cyclobutyl]ethylamine (Formula I R₁ =Me;R₂ =H; R₃ =Me; R₄ =H; R₅ =4--Cl and R₆ =H).

EXAMPLE 21

Sodium borohydride (2.0 g) was added to solution of1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine (1.5 g prepared bytreating the product of Example 1 with aqueous sodium hydroxide) inglacial acetic acid (30 ml). The mixture was heated at 95°-100° C. forsixteen hours and then cooled. Aqueous sodium hydroxide solution wasadded and the reaction mixture extracted with ether. The ether extractwas shaken with 5N hydrochloric acid and the aqueous layer was washedwith ether, basified and extracted with ether. Hydrogen chloride gas waspassed into the ether extract which was evaporated to dryness.Trituration with acetone gaveN-ethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride(m.p. 211°-212° C.) (Formula I R₁ =Me; R₂ =H; R₃ =Et; R₄ =H; R₅ =4--Cland R₆ =3--Cl.)

EXAMPLE 22

A mixture of N-ethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine (0.5g prepared by treating the product of Example 21 with aqueous sodiumhydroxide) and acetic anhydride (1 ml) was heated at 40°-45° C. forthirty minutes. The reaction mixture was basified and extracted withether. The ether extract was washed, dried and evaporated to giveN-acetyl-N-ethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine as anoil.

This oil was dissolved in tetrahydrofuran (10 ml) andborane-dimethylsulphide complex (0.5 ml) added dropwise. The reactionmixture was stirred at room temperature for two hours and then heated to35°-40° C. for thirty minutes. After cooling the reaction mixture wasbasified and extracted with ether. Hydrogen chloride gas was passed intothe dried ether extract which was evaporated to dryness. Triturationwith ether gaveN,N-diethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride(m.p. 199°-201° C.). (Formula I R₁ =Me; R₂ =H; R₃, R₄ =Et; R₅ =4--Cl andR₆ =3--Cl).

EXAMPLE 23

A mixture of 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane (2.2 g) preparedas described in Example 1, ammonium acetate (7 g), sodiumcyanoborohydride (0.4 g) and methanol (28 ml) was stirred at roomtemperature for four days. The reaction mixture was poured into amixture of ice and water and the resulting mixture extracted with ether.The ether extract was washed with water, dried and the ether removed toleave 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine as an oil which wasidentified by standard analytical techniques as the compound of Example1 in the form of its free base.

EXAMPLE 24

A mixture of 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane (4.86 g)prepared as described in Example 1, hydroxylamine hydrochloride (1.6 g),sodium acetate trihydrate (3.3 g), industrial methylated spirit (15 ml)and water (2 ml) was heated under reflux for twenty hours. The cooledreaction mixture was poured into water and the oil which separated wascooled to give a solid which was recrystallised from industrialmethylated spirit to give 1-acetyl-1-(3,4-dichlorophenyl)cyclobutaneoxime (m.p. 120°-121° C.).

A solution of the oxime prepared above (4.0 g) in ether (50 ml) wasadded slowly to a stirred suspension of lithium aluminium hydride (0.9g) in ether (50 ml) under nitrogen. The mixture was heated under refluxfor one hour and, after cooling, water and then a 20% aqueous solutionof Rochelle's salt (potassium sodium tartrate tetrahydrate) (27 ml) anda 10% aqueous solution of sodium hydroxide (6 ml) added. The reactionmixture was stirred for one hour and then continuously extracted withether during eighteen hours. The ether extract was dried and the etherremoved to leave a solid from which1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine was separated by highpressure liquid chromatography. The product was identified by standardanalytical techniques as the compound of Example 1 in the form of itsfree base.

EXAMPLE 25

A 1M solution of diisobutylaliminohydride in hexane (200 ml) was addedunder nitrogen to a solution of 1-phenyl-1-cyclobutane carbonitrile(31.4 g) in either (100 ml) at a temperature below -30° C. Thetemperature was maintained below 0° C. for thirty minutes and 5Nhydrochloric acid (200 ml) at a temperature of -10° C. added. Thereaction mixture was washed with petroleum ether (b.p. 60°-80° C.) andthen warmed to 40° C. The reaction mixture was extracted with petroleumether (b.p. 60°-80° C.) and the extract dried and evaporated to yield1-phenyl-1-cyclobutane-carbaldehyde as an oil.

Methylamine was bubbled through a solution of the aldehyde (9.4 g)prepared as above in toluene (100 ml) whilst the temperature of thereaction mixture was maintained below 0° C. Magnesium sulphate (20 g)which had been dried over a flame and then cooled under nitrogen wasadded to the reaction mixture which was left for sixteen hours at roomtemperature before being filtered. The toluene was then removed byevaporation and the residue dissolved in ether (50 ml). This solutionwas added to a solution of propyllithium prepared by slowly addingexcess propyl bromide (12.8 g) to a suspension of lithium (1.26 g) inether (50 ml). The resulting mixture was left for sixteen hours at roomtemperature. A trace of unreacted lithium was removed by filtration andthe filter washed with ether, water and then 5N hydrochloric acid. Thefiltrate and washings were heated on a steam bath for one hour. Aftercooling the reaction mixture was washed with ether and the aqueous layerwas basified using aqueous sodium hydroxide solution. The reactionmixture was extracted with ether and the extract dried and the etherremoved to give a residue from whichN-methyl-1-(1-phenylcyclobutyl)butylamine (b.p. 80°-86°/0.1 mm Hg.) wasdistilled.

The amine (2.3 g) prepared as described above was dissolved in ether (40ml) and hydrogen chloride gas passed through the solution to precipitateN-methyl-1-(1-phenylcyclobutyl)butylamine hydrochloride (m.p. 196°-197°C.). (Formula I R₁ =propyl; R₂ =H; R₃ =Me; R₄, R₅ and R₆ are H.)

EXAMPLE 26

A solution of 1-(3-chloro-5-methylphenyl)-1-cyclobutanecarbonitrile (8.0g) in ether (40 ml) was added to a solution of propyl magnesium bromide[prepared by the reaction of 1-bromopropane (6.7 g) and magnesium (1.3g)] in ether (80 ml) and the mixture heated under reflux for two and ahalf hours. Two thirds of the ether was evaporated off and then, aftercooling, a solution of sodium borohydride (3.5 g) in ethanol (150 ml)added. The mixture was maintained at 50° C. for one hour and water (50ml) and then 5N hydrochloric acid (50 ml) added. The ether layer wasseparated, dried and evaporated to yield a solid which wasrecrystallised from propan-2-ol to give1-[1-(3-chloro-5-methylphenyl)cyclobutyl]butylamine hydrochloride (m.p.145°-146° C.).

The hydrochloride salt prepared as above was shaken with ether and 5Nsodium hydroxide solution and the ether layer evaporated to give theprimary amine which was converted intoN,N-dimethyl-1-[1-(3-chloro-5-methylphenyl)cyclobutyl]butylaminehydrochloride (m.p. 148° C.) (Formula I R₁ =propyl; R₂ =H; R₃ and R₄=Me; R₅ =3--Cl and R₆ =5--Me) in a similar manner to that described inExample 2.

EXAMPLE 27

1-Acetyl-1-(3,4-dichlorophenyl)cyclobutane prepared as described inExample 1 (4.86 g) and cyclohexylamine (2.28 ml) were heated and stirredunder reflux for 30 minutes. Stirring and heating was continued on anoil bath at 145° C. for 3 hours. The product was cooled to ambienttemperature, dissolved in methanol (50 ml) and sodium borohydride (0.8g) added. The mixture was stirred at ambient temperature for twentyhours and then poured into water and the resulting mixture extractedwith ether. The ether extract was washed with water and dried. Afterremoval of the solventN-cyclohexyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine (b.p.144°-156°/0.6 mm Hg) was obtained by distillation (Formula I R₁ =Me; R₂=H; R₃ =cyclohexyl; R₄ =H; R₅ =4--Cl; R₆ =3--Cl).

EXAMPLE 28

Pharmaceutical compositions containing any one of the compounds offormula I disclosed in Examples 1 to 27 are prepared in the followingmanner.

EXAMPLE 28(a)

Tablets are prepared from the following ingredients:

    ______________________________________                                                       Parts by Weight                                                ______________________________________                                        Active Ingredient                                                                              50.0                                                         Lactose          78.5                                                         Polyvinylpyrrolidone                                                                           5.0                                                          Maize Starch     15.0                                                         Magnesium Stearate                                                                             1.5                                                          ______________________________________                                    

The active ingredient, the lactose and some of the starch are mixed andgranulated with a solution of the polyvinylpyrrolidone in ethanol. Thegranulate is mixed with the stearic acid and the rest of the starch andthe mixture is compressed in a tabletting machine to give tabletscontaining 50.0 mg. of the active ingredient.

EXAMPLE 28(b)

Capsules are prepared in the following way. A mixture of the activeingredient (45 parts by weight) and lactose powder (205 parts by weight)is filled into hard gelatin capsules, each capsule containing 45 mg. ofthe active ingredient.

EXAMPLE 28(c)

In the preparation of enteric coated tablets, the tablets described inExample 28(a) are given a thin coat of shellac varnish, followed by 20coats of cellulose acetate phthalate in a manner well known in the art.In a similar manner the capsules of Example 28(b) may be provided withan enteric coating.

EXAMPLE 28(d)

Vials containing a solution of water-soluble compounds of the presentinvention suitable for injection are prepared from the followingingredients:

    ______________________________________                                        Active Ingredient      1100 g.                                                Mannitol               1100 g.                                                Water, freshly distilled                                                                             to 11 liters                                           ______________________________________                                    

The active ingredient and mannitol are dissolved in some of the waterand the volume of the solution is adjusted to 11 liters. The resultingsolution is sterilised by filtration and filled into sterile vials eachcontaining 1.65 ml. of solution.

EXAMPLE 28(e)

In the preparation of suppositories, 100 parts by weight of the finelyground active ingredient is incorporated in 1214 parts by weight oftriglyceride suppository base and the mixture is formed intosuppositories each containing 100 mg. of the active ingredient.

In the preceding Examples novel ketones of formula V have been disclosedin which R₁, R₅ and R₆ have the meaning given in Examples 1, 1(a) to1(e), 3, 4, 4(a) to 4(e), 6, 7, 7(a) to 7(d) 9, 9(a) to 9(n), 10, 10(a)to 10(z), 10(aa), 10(bb), 11(i), 11(k) and 11(l). These novel ketones offormula V are prepared by hydrolysis of novel imines of formula XI inwhich Y=MgBr and R₁, R₅ and R₆ have the meaning given in the Examplesspecified above.

In the preceding Examples novel cyano compounds of formula XII aredisclosed in which R₅ and R₆ have the meaning given in Examples 1, 1(d),1(e), 4(g), 9(e), 9(m), 10(k), 10(e), 10(p), 10(r), 10(v), 10(y), 10(z),10(aa), 10(bb), 11(k), 11(l) and 26.

In the preceding Examples novel formamides of formula XVII are disclosedin which R₁, R₃, R₅, R₆, R₇, R₈ have the meaning given in Examples 1,1(a) to 1(e), 3, 4, 4(a) to 4(e), 6, 7, 7(a) to 7(d), 9, 9(a) to 9(n),10, 10(a) to 10(z), 10(aa), 10(bb), 11(i), 11(k), 11(l).

We claim:
 1. A compound of formula III ##STR34## or a pharmaceuticallyacceptable salt thereof in which R₁ is methyl or ethyl, R₂ is H ormethyl, R₃ and R₄ are each selected from the group consisting of H,methyl and ethyl, or R₃ is a cycloalkyl group containing 3 to 6 carbonatoms and R₄ is H, or R₃ and R₄ together with the nitrogen atom to whichthey are attached form a pyrrolidinyl ring, and R₅ and R₆ together withthe phenyl ring to which they are attached form a 4-chlorophenyl,4-bromophenyl, 4-iodophenyl, 3-chlorophenyl, 3-bromophenyl,3,4-dichlorophenyl, 4-chloro-3-fluorophenyl,4-chloro-3-trifluoromethylphenyl, 4-biphenylyl, 2-naphthyl or2-phenanthryl group.
 2. A compound according to claim 1 which isN-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine or apharmaceutically acceptable salt thereof.
 3. A compound according toclaim 1 which is 1-[1-(4-chlorophenyl)cyclobutyl]ethylamine or apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 1 which is N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]ethylamine ora pharmaceutically acceptable salt thereof.
 5. A compound according toclaim 1 which is N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]ethylamineor a pharmaceutically acceptable salt thereof.
 6. A compound accordingto claim 1 or a pharmaceutically acceptable salt thereof in which R₁ ismethyl; R₂ is H; R₃ is H, methyl or ethyl; R₄ is H, methyl or ethyl; R₅is chloro; R₆ is H or chloro.
 7. A compound according to claim 6 whichis 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine or a pharmaceuticallyacceptable salt thereof.
 8. A compound according to claim 6 which isN,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-ethylamine or apharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition useful for treating depression in humans which comprises anantidepressently effective amount of a compound of the formula III##STR35## or a pharmaceutically acceptable salt thereof in which R₁ ismethyl or ethyl, R₂ is H or methyl, R₃ and R₄ are each selected from thegroup consisting of H, methyl and ethyl, or R₃ is a cycloalkyl groupcontaining 3 to 6 carbon atoms and R₄ is H, or R₃ and R₄ together withthe nitrogen atom to which they are attached form a pyrrolidinyl ring,and R₅ and R₆ together with the phenyl ring to which they are attachedform a 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 3-chlorophenyl,3-bromophenyl, 3,4-dichlorophenyl, 4-chloro-3-fluorophenyl,4-chloro-3-trifluoromethylphenyl, 4-biphenylyl, 2-naphthyl or2-phenanthryl group, in combination with a pharmaceutically acceptablecarrier.
 10. A composition according to claim 9 in whichN-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine or apharmaceutically acceptable salt thereof.
 11. A composition according toclaim 9 which is 1-[1-(4-chlorophenyl)cyclobutyl]ethylamine or apharmaceutically acceptable salt thereof.
 12. A composition according toclaim 9 which is N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]ethylamine ora pharmaceutically acceptable salt thereof.
 13. A composition accordingto claim 9 which isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]ethylamine or apharmaceutically acceptable salt thereof.
 14. A composition according toclaim 9 wherein R₁ is methyl, R₂ is H, R₃ is H, methyl or ethyl, R₄ isH, methyl or ethyl, R₅ is chloro and R₆ is H or chloro.
 15. Acomposition according to claim 14 wherein the compund is1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine or a pharmaceuticallyacceptable salt thereof.
 16. A composition according to claim 14 whereinthe compound isN,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-ethylamine or apharmaceutically acceptable salt thereof.
 17. A method of treatingdepression in humans which comprises administering to a human or animalin need thereof an antidepressently effective amount of a compound ofthe formula III ##STR36## or a pharmaceutically acceptaable salt thereofin which R₁ is methyl or ethyl, R₂ is H or methyl, R₃ and R₄ are eachselected from the group consisting of H, methyl and ethyl, or R₃ is acycloalkyl group containing 3 to 6 carbon atoms and R₄ is H, or R₃ andR₄ together with the nitrogen atom to which they are attached form apyrrolidinyl ring, and R₅ and R₆ together with the phenyl ring to whichthey are attached form a 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl,3-chlorophenyl, 3-bromophenyl, 3,4-dichlorophenyl,4-chloro-3-fluorophenyl, 4-chloro-3-trifluoromethylphenyl, 4-biphenylyl,2-naphthyl or 2-phenanthryl group, in combination with apharmaceutically acceptable carrier.
 18. A method according to claim 17wherein R₁ is methyl, R₂ is H, R₃ is H, methyl or ethyl, R₄ is H, methylor ethyl, R₅ is chloro and R₆ is H or chloro.
 19. A method according toclaim 17 in whichN-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine or apharmaceutically acceptable salt thereof.
 20. A method according toclaim 17 which is 1-[1-(4-chlorophenyl)cyclobutyl]ethylamine or apharmaceutically acceptable salt thereof.
 21. A method according toclaim 17 which is N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]ethylamine ora pharmaceutically acceptable salt thereof.
 22. A method according toclaim 17 which isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]ethylamine or apharmaceutically acceptable salt thereof.